A novel mTOR inhibitor is efficacious in a murine model of colitis.
Ulcerative colitis is an autoimmune-inflammatory disease characterized by increased proliferation of colonic epithelial cells, dysregulation of signal transduction pathways, elevated mucosal T cell activation, increased production of proinflammatory cytokines, and enhanced leukocyte infiltration into colonic interstitium. Several compounds that possess antiproliferative properties and/or inhibit cytokine production exhibit a therapeutic effect in murine models of colitis. Mammalian target of rapamycin (mTOR), a protein kinase regulating cell proliferation, is implicated in colon carcinogenesis. In this study, we report that a novel haloacyl aminopyridine-based molecule (P2281) is a mTOR inhibitor and is efficacious in a murine model of human colitis. In vitro studies using Western blot analysis and cell-based ELISA assays showed that P2281 inhibits mTOR activity in colon cancer cells. In vitro and in vivo assays of proinflammatory cytokine production revealed that P2281 diminishes induced IFN-gamma production but not TNF-alpha production, indicating preferential inhibitory effects of P2281 on T cell function. In the dextran sulfate sodium (DSS) model of colitis, 1) macroscopic colon observations demonstrated that P2281 significantly inhibited DSS-induced weight loss, improved rectal bleeding index, decreased disease activity index, and reversed DSS-induced shortening of the colon; 2) histological analyses of colonic tissues revealed that P2281 distinctly attenuated DSS-induced edema, prominently diminished the leukocyte infiltration in the colonic mucosa, and resulted in protection against DSS-induced crypt damage; and 3) Western blot analysis showed that P2281 blocks DSS-induced activation of mTOR. Collectively, these results provide direct evidence that P2281, a novel mTOR inhibitor, suppresses DSS-induced colitis by inhibiting T cell function and is a potential therapeutic for colitis. Given that compounds with anticancer activity show promising anti-inflammatory efficacy, our findings reinforce the cross-therapeutic functionality of potential drugs.
Bhonde
Mandar R
MR
Dept. of Pharmacology, Piramal Life Sciences Limited, 1 Nirlon Complex, Off Western Express Highway, Goregaon (East Mumbai - 400063, Maharashtra, India. nilesh.dagia@piramal.com).
Gupte
Ravindra D
RD
Dadarkar
Shruta D
SD
Jadhav
Mahesh G
MG
Tannu
Aditi A
AA
Bhatt
Pooja
P
Bhatia
Dimple R
DR
Desai
Nikesh K
NK
Deore
Vijaykumar
V
Yewalkar
Nilambari
N
Vishwakarma
Ram A
RA
Sharma
Somesh
S
Kumar
Sanjay
S
Dagia
Nilesh M
NM
D000631:Aminopyridines / Q000627:therapeutic use*; D000813:Anilides / Q000627:therapeutic use*; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D058570:TOR Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
C534868:2-chloro-N-(6-cyanopyridin-3-yl)propanamide; D000631:Aminopyridines; D000813:Anilides; D002352:Carrier Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D016264:Dextran Sulfate; D017853:Phosphotransferases (Alcohol Group Acceptor); C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases